Biopolymers derived from hydrolyzable diacid fats

ABSTRACT

A monomeric diacid derivative includes at least two fatty acids coupled by a hydrolytically or enzymatically degradable bond. In a biological environment, the bond degrades forming naturally occurring fatty acid products thereby allowing elimination.

TECHNICAL FIELD

This invention relates to the area of organic synthesis and, inparticular, the synthesis of biocompatible polymers.

BACKGROUND OF THE INVENTION

Over the last 20 years, many classes of biodegradable polymers have beenunder development for a wide variety of biomedical applications. (Domb,et al, 1994) The most actively pursued biomaterials include: thelactide/glycolide copolymers, polyorthoesters, polycaprolactones,polyphosphazenes and Polyanhydrides. (Domb, et l, 1994, 1992, 1993) Oneof the widely studied applications of these polymers is their use inimplantable drug delivery systems. For this application, polyanhydridesare a unique class of polymers because some of them demonstrate a nearzero order drug release and a relatively rapid biodegradation in vivo.

Some of the desired physico-chemical and mechanical properties in asingle polymer that could be used in an implantable or injectable drugdelivery system are:

a. hydrophobic enough so that the drug is released in a predictable andcontrolled way;

b. be biocompatible when implanted in the target organ;

c. being completely eliminated from the implantation site in apredictable time;

d. suitable physical properties for device fabrication properties (lowmelting point, usually below 100° C. and soluble in common organicsolvents);

e. flexible enough before and during degradation so that it does notcrumble or fragment during use; and

f. easy to manufacture at a reasonable cost.

Some of these ideal properties are displayed by some of thepolyanhydrides. For example, poly(carboxyphenoxy propane) [P(CPP)]displays near zero order erosion and release kinetics. (Leong et al1985) However, this polymer displays an extremely slow degradation rate,and it is estimated that a drug delivery device prepared from P(CPP)would take almost three years to completely degrade in vivo.

In U.S. Pat. No. 5,171,812, a class of aliphatic copolyanhydrides wassynthesized from dimers and trimers of unsaturated fatty acids (FAD andFAT, respectively) with sebacic acid. This class of polymers weredemonstrated to have the properties suitable for developing varioustypes implantable drug delivery devices, including: microspheres, films,rods, and beads.

In a recent publication, Domb and Manis, 1993), a class of aliphaticcopolyanhydrides was synthesized from nonlinear hydrophobic dimers (FAD)of erucic acid and sebacic acid (SA). This class had some bitcompatiblecharacteristics even though there was a rapid partial degradation withinthe first ten days with the release of the SA component, a residue whichis mostly the FAD comonomer remains and is not easily degraded.

Although these polymers were found suitable for drug deliveryapplications both in vivo and in vitro, studies in dogs showed that whenimplanted in muscle, the polymer degraded to the synthetic fatty aciddimer which was not eliminated from the implantation site even after sixmonths. This semisynthetic fatty acid dimer is not easily metabolized inthe body because it contains a non-natural structure of a C--C bridge(Structure 1) which is difficult to be metabolized by body enzymes.##STR1##

The FAD and related oligomers of fatty acids are the coupling productsof two or more unsaturated fatty acids in which the original fatty acidsare connected via a chemically stable C--C bond (non-hydrolyzable).Because the oligomerized fatty acids contain a non-natural structure(C--C branching points), they may not be eliminated at the same rate andcapacity as natural fatty acids, which are readily eliminated from thebody by a β-oxidation process.

SUMMARY OF THE INVENTION AND ADVANTAGES

According to the present invention, a monomeric diacid derivativecomprising at least two fatty acids coupled by a hydrolytically orenzymatically degradable bond is formed. In a biological environment,the bond degrades forming naturally occurring fatty acid productsthereby allowing elimination.

In general, the monomeric diacid derivative has the structure ##STR2##wherein R, R¹ and R² are aliphatic organic residues with 0 to 20 carbonatoms and can be the same or different, X is an enzymatically orhydrolytically degradable bond selected from the group consisting ofester, amide, urethane, acetal, urea, and carbonate bonds can be formed.

The absence of stable C--C nonhydroyzable branching bonds allows thesemonomers to be first hydrolyzed to the respective natural acids and thenrapidly eliminated since naturally occurring fatty acids are formed andare readily eliminated from the body via β-oxidation.

BRIEF DESCRIPTION OF THE DRAWINGS

Other advantages of the present invention will be readily appreciated asthe same becomes better understood by reference to the followingdetailed description when considered in connection with the accompanyingdrawings wherein:

FIG. 1 is a graph showing hydrolytic degradation of polymers based onricinoleic acid as determined by weight loss and conversion of anhydrideto acid groups, degradation being determined in 0.1M phosphate buffer pH7.4 at 37° C.;

FIG. 2 is a graph showing in vitro release of ciprofloxacin fromricinoleic acid maleate-based polymeric devices, drug release beingdetermined in 0.1M phosphate buffer pH 7.4 at 37° C; and

FIG. 3 is a graph showing in vitro release of ciprofloxacin fromricinoleic acid maleate-sebacic acid copolymer based polymeric devices,drug release being determined in 0.1M phosphate buffer pH 7.4 at 37° C.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention relates to biodegradable polymers containing novelhydrolyzable diacid fats which provide hydrophobicity and improvedphysical and mechanical properties to the polymers as compared tobiopolymers that do not contain these monomeric units, and yet arecompletely degradable to natural products when exposed to biologicalenvironments.

In searching for an alternative hydrophobic monomer that possessessimilar properties to the FAD but is more readily eliminated from thebody, i.e. does not contain a stable C-C coupling bond, applicants havesynthesized a new class of fatty-acid-based-diacid monomers with similarproperties to the FAD monomer but that hydrolyze to the natural fattyacid.

The diacids were synthesized from fatty acids containing a hydroxyl oramine side group and aliphatic diacid derivatives. The general structureof these monomers is: ##STR3## wherein R, R¹ and R² are aliphaticorganic residues with 0 to 20 carbon atoms and can be the same ordifferent, X is an enzymatically or hydrolytically degradable bondselected from the group consisting of ester, amide, urethane, acetal,urea, or carbonate bonds can be formed. Examples of other usefulmonomers are diacid derivatives of tartaric acid andglycerylmonostearate.

These monomers are synthesized, for example, from natural hydroxy fattyacids which are reacted with dicarboxylic acid derivatives, such ascyclic anhydrides, to provide diacid monomers suitable for anhydride andester polymerization. The reaction is conducted in an organic solventwhere the hydroxy acid is reacted under reflux with the cyclicanhydride. When other reactive acids are used, the reaction conditionsshould be adjusted. The natural molecules are therefore linked by anhydrolyzable bond which include: ester, amide, imide, orthoester,carbonate, urethane, urea or phosphate ester. These diacid fats can bepolymerized or copolymerized into a polyanhydride or polyester and formpolymers that are, in general, of a low melting point (below 100° C.),soluble in common organic solvents, and pliable materials.

This invention is demonstrated by the synthesis and characterization ofpolymers based on ricinoleic acid. Natural hydroxy fatty acids, such as12-hydroxy stearic acid and ricinoleic acid were reacted with cyclicanhydrides such as succinic or maleic anhydride, to provide diacidmonomers suitable for anhydride and ester polymerization. These monomersare expected to degrade in vivo into their fatty acid and succinic acidcounterparts since they are bound by a hydrolyzable ester bond. Thestructures of the diacids are: ##STR4##

Diacids were synthesized based on Ricinoleic acid, 12-hydroxy oleicacid. The hydroxyl group was reacted with maleic anhydride to formricinoleic acid maleate (I). Hydrogenolysis of this diacid forms thesaturated derivative, 12-hydroxy stearic acid succinate (II). A thirddiacid monomer was synthesized from the reaction between 12-hydroxystearic acid and maleic anhydride (III). These diacid monomers wereincorporated into a polyanhydride or polyester and used as carriers fordrugs.

The diacid fats used as examples in this application have the followinggeneral structures: ##STR5## where: x=5-25; y=1-12; v+w=25;Z=CO,CO--O,CO--NH; and M=O--CO,O--CO--O,O--CO--NH, O--PO₂ --O,NH--CO.

These monomers are diacid derivatives of monoglycerides, tartaric acidand fatty acids having an additional functional group with one or morenatural molecules linked by an hydrolyzable bond which include: ester,amide, imide, orthoester, carbonate, urethane, urea or phosphate ester.These diacid fats can be polymerized or copolymerized into apolyanhydride or polyester and form polymers that are, in general, of alow melting point (below 100° C.) soluble in common organic solvents,and pliable materials that are useful in making biodegradable medicaldevices. For example, microspheres loaded with drugs can be prepared forthe delivery of drugs in vivo and in vitro. Because these monomershydrolyze in a biological environment to their original natural and safecounterparts, they are biocompatible and their elimination time afterpolymer degradation is within three months.

These monomers are polymerized into polyanhydrides and into polyestersas described in the examples.

Additionally, these diacid fats can be used as plasticizing componentsin plastics such as nylon, polyurethane as substitute for oligomerizedfatty acids with the advantage of simple structure and ease ofpreparation.

The present invention allows the preparation of a drug release systemwhich will deliver a pharmacologically effective amount of a drug. Thedrug is held or entrapped in a polymer matrix. The matrix essentiallyconsists of repeating units of a monomeric diacid derivative comprisingat least two fatty acids coupled by a hydrolytically or enzymaticallydegradable bond whereby said degradable bond in a biological environmentdegrades forming naturally occurring fatty acid products. As the bondsdegrade the drug is released. The bonds can be ester, amide, urethane,urea and carbonate bonds.

The drugs in solid form are melted or dispersed in the polymer to form amatrix, small molecules, as well as large molecules, such as peptides,proteins, and antibodies, can be delivered from the polymer matrix. Theduration of drug release is mostly affected by the hydrophobicity of thedrug, drug loading, and polymer composition.

Further, the present invention can be used as a biocompatible,biodegradable, implantable material essentially consisting of repeatingunits of a monomeric diacid derivative comprising at least two fattyacids coupled by a hydrolytically or enzymatically degradable bondwhereby said degradable bond in a biological environment degradesforming naturally occurring fatty acid products. The bonds can be ester,amide, urethane, urea and carbonate bonds. The implantable material canbe used to form dressings, sutures and the like that need to beimplanted but not remain in the body. For example, they can be used asfilms for surgical adhesion prevention by placing the polymer film atthe abraded area during surgery.

In general, the method for synthesizing the biodegradable polymercontaining hydrolyzable diacid fats requires the preparation of at leastone highly pure prepolymer of monomeric diacid derivative comprising atleast two fatty acids coupled by a hydrolytically or enzymaticallydegradable bond. The prepolymer is then polymerized at a temperature andreaction time to form a polyanhydride or polyester of an appropriatemolecular weight. The polymerization is stopped when a molecular weightbetween 10,000 and 100,000 is obtained for the needed application ordevice.

A copolymer is formed from at least two highly pure prepolymerspolymerized together as described above. U.S. Pat. No. 4,757,128 to Dombet al., issued July 1988, discloses examples of classes of monomers thatcan be copolymerized with the monomers of the present invention to formcopolyanhydrides. Typical and useful co-monomers are the aliphaticdiacid such as adipic, subernic, dodedecane dicarboxylic acid. Otherco-monomers can be iso-phthalic acid, terephthalic acid,carboxphenoxypropane. The copolymer of RAM with subernic acid gave a Mwof 32,000, the copolymer with iso-phthalic acid gave a Mw of 24,000.

The ricinoleic acid maleate of the present invention are useful asplasticizer for plastic modeling. The following is the preferred methodof preparing the formulation.

Ricinoleic acid maleate containing plasticizer

Low volatile polyester mixtures based on Ricinoleic acid maleate areuseful as plasticizer for plastic modeling:

A mixture of adipic acid (58 grams), ricinoleic acid maleate (7 grams),propylene glycol (38 grams), and n-hexanol (13 grams) was heated at 140°C. for five hours while water was distilled. To the reaction mixture,0.05% of stannous octoate was added as catalyst and the reactiontemperature was increased to 180° C. and a vacuum of 0.1 mm Hg wasapplied for an additional three hours. The resulting viscous polymer hada molecular weight of 700 as determined by gel permeationchromatography. The resulting oligomer was mixed 30 weight percent withpolyvinylchloride (PVC) to form a flexible sheet which had a loss of 0.5weight percent in the volatility test at 105° C. for three days comparedto 1.2 to 2.5% with the phthalate plasticizer. Other plasticizers wereprepared similarly using hydroxy stearic acid succinate or hydroxystearic acid maleate instead of ricinoleic acid maleate.

Preparation of hydrophilic plasticizer: Ricinoleic acid maleate wasreacted with two equivalents of poly(ethylene glycol) MW.tbd. 2,000 intoluene with 1% H3P04 (85% concentration) as catalyst. The reaction wascontinued for five hours at 110° C. Toluene was evaporated to dryness toform an oily material. The material was mixed in PVC to form a flexiblesheet which had a loss of 0.6% at 105° C. for three days volatilitytest.

The following examples illustrate the preparation of and use of themonomers and polymers of the present invention:

Materials and Methods

The following compounds were used: ricinoleic acid (Kodak 91% pure),maleic anhydride (BDH, 99.5%), Sebacic acid (Aldrich 99%), aceticanhydride, toluene (dried by azeotropic distillation before use), EtOH(abs.), CH₂ Cl₂, and CHCl₃ (all Frutarom analytical grade).

IR spectroscopy was performed on an Analect Instruments FTIRspectrometer model fx-6160 using a Data system MAP-67. Monomer,prepolymer, and polymer samples were film cast onto NaCl plates ordissolved in chloroform and placed in a NaCl cell.

Ultraviolet spectroscopy was performed on a Kontron® Instruments Uvikonspectrophotometer model 930.

Melting points were determined on an Electrothermal melting pointapparatus. Melt transition temperatures and degree of crystallinity weredetermined by a Perkin Elmer DSC 7 differential scanning calorimeter,calibrated with zinc and indium standards. The heating rate was 20°C./min for all the polymers, under nitrogen atmosphere.

Molecular weights of the polymers and prepolymers were estimated on aGPC system composed of a Spectra Physics P1000 pump, Applied Biosystems759A Absorbance UV detector at 254 nm, Spectra Physics Data Jetinjector, and a WINner/286 data analysis computer system. Samples wereeluted in dichloromethane through a linear Styroget, 10⁴ Å pore size, ata flow rate of 1 ml/min and monitored at 254 nm. Molecular weight ofpolymers were determined relative to polystyrene standards(Polysciences, Pa.), with a molecular weight range of 400 to 1,500,000using Maxima 840 computer program (Waters, Mass.).

¹ H-NMR spectra were obtained on a Varian 300 MHz spectrometer at 23° C.using deuterated chloroform/TMS solvent. Chemical shifts were expressedin ppm downfield from Me₄ Si as an internal standard. The values aregiven in d scale.

Tensile strength measurements were attained using an Instron TensileTester Model 1114 at room temperature.

Catalytic hydrogenation was performed using 3% Pd on activated carbon(Aldrich) using a Parr apparatus. Evaporation's were carried out on aBuchi RE 111 Rotavapor.

Examples 1. Monomer and Polymer Synthesis

Ricinoleic acid maleate (RAM).

A solution of ricinoleic acid (144 g, 0.48 mol) and maleic anhydride (61g, 0.61 mol) in toluene (350 ml) was stirred at 80°-90° C. overnight.The excess of maleic anhydride which precipitated was removed byfiltration. The solution was washed four times with distilled water,dried over MgSO₄ and evaporated to dryness to give 140.92 g (73%) ofproduct as a dark orange oil. Titration (using THF as solvent andphenolphthalein as indicator) with 0.1 N NaOH showed 88% diacid product;IR 1740, 1715 cm⁻¹ ; ¹ H-NMR 6.33 (dd, 2H, HOOC--CH═CH--COO--) , 5.45(m, 1H, C--CH═CH--C) , 5.28 (m, 1H, C--CH═CH--C), 5.00 (quintet, 1H,methine), 2.33 (m, 2H, CH₂ --COOH), 2.00 (dd, 2H, OCO--C--CH₂ --CH═CH) ,1.60 (m, 4H, CH₂ -- CH₂ --COOH and COO--CH--CH₂ --CH₂), 1.25 (broad d,18H, aliphatic methylenes), 0.83 (t, 3H, --CH₃)

12-hydroxysteric acid succinate (HSAS).

A solution of RAM (50 g. 0.13 mol) in abs. EtOH (˜100 ml) washydrogenated over 3 g Pd/C at 85 atm overnight. The catalyst wasfiltered off, and the solution was evaporated to dryness yielding 46.83g (94%) of an oily orange liquid, which upon cooling to room temperaturesolidified to an off- white solid which was dissolved in hot EtOH andleft to recrystallize in the freezer for two weeks. The product wasfiltered and dried to give 37.0 g (74%), mp 50°-52° C; IR 1740, 1715cm⁻¹ ; ¹ H-NMR 4.88 (quintet, 1H, methine), 2.77 (t, 2H, HOCO--CH₂--CH2--COO--CH), 2.63 (t, 2H, HOCO--CH₂ --CH₂ --COO--CH), 2.42 (t, 2H,CH₂ --COOH), 1.62 (m, 4H, CH₂ --CH--OCO--CH₂), 1.52 (m, 2H, CH₂ --CH₂--COOCO) , 1.23 (m, 22H, aliphatic methylenes), 0.85 (t, 3H, CH₂ --CH₃)

12-hydroxystearic acid maleate (HSAM).

A solution of ricinoleic acid (50 g, 0.17 mol) in abs. EtOH (˜100 ml)was hydrogenated over 3 g Pd/C at 80 atm overnight. The solidifiedproduct was dissolved in CH₂ Cl₂, and the catalyst was removed byfiltration. The solution was evaporated yielding 50 g (100%) of product.Recrystallization from EtOH gave 35.0 g (70%). The FTIR and NMR spectrawere similar to those described in the Aldrich 93 catalogs, mp 73°-75 C.(lit: Aldrich 93 catalog 80°-81° C.). A solution of 12-hydroxystearicacid (34.45 g, 0.11 mol) and maleic anhydride (14.5 g, 0.148 mol) intoluene (240 ml) was stirred at 88° C. overnight. The solution waswashed four times with distilled water, dried over MgSO₄ and evaporatedto dryness to yield 40.0 g (88%). Titration (using THF as solvent andphenolphthalein as indicator) with 0.1N NaOH showed 96% diacid product;IR 1740, 1715 cm⁻¹ ; ¹ H-NMR 6.38 (d, 2H, COCH═CHCO), 5.02 (t, 1H,CHOCO), 2.36 (t, 2H, CH₂ COOH), 1.61 (m, 6H, H₂ CCOCHO and CH₂ CH₂COOH), 1.27 (m, 22H, (CH₂)₁₁), 0.88 (t,3H,CH₃).

Preparation of prepolymers.

The prepolymers of sebacic acid (SA) were prepared as previouslydescribed. (Domb and Langer, 1987). Briefly, sebacic acid prepolymer wasprepared from the purified diacid monomer by refluxing it in excessacetic anhydride for 30 minutes and evaporating it to dryness. The hotclear viscous residue was dissolved in dichloromethane and theprepolymer was precipitated in a mixture of hexane/isopropyl ether(1:1). The solid was collected by filtration and dried by vacuum at roomtemperature.

Prepolymers of the fatty acid ester based monomers were prepared asfollows: Solutions of each monomer dissolved in acetic anhydride (120°C., 1:5 w/v) were stirred under reflux for 20 min.

The RAM prepolymer solution was evaporated to dryness to give an orangeoil product. Mw-3800 Mn-3520; IR 2900, 2850, 1810, 1720 cm⁻¹ ; ¹ H-NMR6.30 (dd, 2H, CO--CH═CH--CO), 5.42 (d, 1H, CH═CH), 5.38 (d, 1H, CH═CH),4.98 (quintet, 1H, methine), 2.45 (t, 2H when prepolymer ishead-to-tail, CH₂ --COO--), 2.40 (t, 2H when prepolymer is head-to-head,CH₂ --COO--) , 2.32 (s, 3H, CH₃ --COOCO--CH═CH) , 2.21 (s, 3H, CH₃--COOCO--CH₂ --CH₂), 2.00 (dd, 2H, C--CH₂ --CH═CH) , 2.30 (m, 2H,CH═CH--CH₂ CH₂ --) 1.60 (m, 4H, CH₂ --CH₂ --COOCO-- andCH═CH--COO--CH--CH₂ --CH₂), 1.30 (broad d, 16H, aliphatic methylenes)0.87 (t, 3H, CH₂ --CH₃). The HSAS prepolymer gave a semisolid off-whiteproduct. Mw-1788 Mn-1382; IR 2900, 2850 1820, 1730 cm⁻¹ ; ¹ H-NMR 4.88(quintet, 1H, methine), 2.77 (t, 2H, COOCO--CH₂ --CH₂ --COO--CH), 2.65(t, 2H, COOCO--CH₂ --CH₂ --COO--CH), 2.44 (t, 2H, CH₂ --COOCO), 1.65 (m,4H, CH₂ --CH--OCO--CH₂ --), 1.55 (quintet, 2H, CH₂ --CH₂ --COOCO) 1.25(m, 22H, aliphatic methylenes), 0.85 (t, 3H, CH₂ --CH₃).

The HSAM prepolymer gave a viscous oil. Mw-1788 Mn-1382; IR 2900, 2850,1820, 1730 cm⁻¹, ¹ H- NMR 6.26 (dd, 2H, CO--CH═CH--CO), 4.92 (quintet,1H, methine), 2.47 (t, 2H when prepolymer is head-to-tail, CH₂ --COO--),2.40 (t, 2H when prepolymer is head-to-head, CH₂ --COO--) , 2.25 (s, 3H,CH₃ --COOCO--CH═CH), 2.17 (s, 3H, CH₃ --COOCO--CH₂ --CH₂), 1.52 (m, 4H,CH₂ --CH₂ --COOCO-- and CH═CH--COO--CH--CH₂ --CH₂), 1.21 (broad, d, 22H,aliphatic methylenes), 0.83 (t, 3H, CH₂ --CH₃).

Preparation of polymers.

The prepolymers underwent melt polycondensation. Typically, RAMprepolymer (10 g, 33 mmol) was placed in a KIMAX® glass tube with a sidearm or a round bottomed flask and polymerized at 180° C. under reducedpressure (0.1-0.5 mm Hg). The polymerization was complete after 90minutes. The by-products, acetic anhydride and acetic acid, were trappedin a liquid N₂ trap. The homopolymers were viscous yellow oils.

Copolymers were prepared similarly by polymerizing a mixture ofprepolymers at 180° C. under reduced pressure. In a typical experiment,RAM prepolymer (5 g, 17 mmol) was mixed with sebacic acid prepolymer(SAdiAc) (5 g, 21mmol) and polymerized at 180° C. under reduced pressurefor 60-90 minutes depending on the amount being polymerized. The crudepolymers were dissolved in CH₂ Cl₂ (1.5 w/v) and filtered into stirringdi-isopropyl ether (100-200 ml). The precipitate was separated byfiltration, washed with di-isopropyl ether, and dried in the Rotavapor.

Molecular weights and thermal characterization of the polymers are shownin Table 1. The IR and ¹ H-NMR of homopolymers of RAM,HSAM,HSAS, and 1:1copolymers with SA (d ppm) are listed in Table 2.

Mechanical Properties.

These series of polymers had similar mechanical properties to the FADclass of polymers. They formed very flexible films with similar strengthas seen in Table 3.

2. Synthesis of polyesters containing fatty diacid monomers.

Biodegradable polyesters were synthesized from the reaction betweenlactide, ricinoleic acid maleate, and propylene glycol in the molarratio 8:1:1 and 1% stannous octoate as polymerization catalyst. Themixture of the monomers were polymerized at 100° C. under nitrogen withconstant stirring. After 24 hours, the temperature was raised to 140°C., the reaction was continued for another 24 hours and then a vacuum of0.1 mm Hg was applied and the reaction was continued for another 8hours. The viscous melt was solidified into a pliable tan mass. Polymerscontaining HSAM and HSAS monomers at various ratios were preparedsimilarly. The data analysis of these polymers is summarized in Table 4.All polymers were soluble in dichloromethane, chloroform, andtetrahydrofuran. IR spectra of the polymers showed esters peaks at 1720nm.

3. Synthesis of distearyl tartaric acid.

Into a flask were placed 100 ml dichlomethane, tartaric acid (0.1 mole),triethylamine (0.4 mole), and stearoyl chloride (0.2 mole). The reactionwas left for 24 hours with constant stirring. The reaction mixture waswashed with 0.1N HCl solution to yield distearyl tartaric acid.

4. In vivo biocompatibility and elimination studies.

The biocompatibility and the elimination time of these new polymers ascompared to poly(FAD-SA) 50:50 and poly(sebacic acid) {PSA} was studiedin rats as follows:

Clean specimens (30 mg, 2×2×4 mm in size) of the following polymers:

1. poly(RAM-SA)30:70,

2. poly (HSAM-SA) 50: 50,

3. poly (HSAS-SA) 50: 50,

4. poly (FAD-SA) 50: 50,

5. Vicril (Ethicon),

6. poly(FAD-SA) 50:50, and

7. poly(sebacic acid) {PSA}

were implanted subcutaneously in four dorsal sites of maleSprague-Dawley rats (250-300 g). Six rats were used in the study andeach rat was implanted randomly with four different specimens. Allanimal work was done under sterile conditions. The polymer specimenswere dipped in 70% alcohol prior to insertion. The animals weresacrificed after 12 and 30 days post implantation, and the implantationsites were examined macroscopically and histologically. The polymerremnants were retrieved and analyzed.

Macroscopically, no swelling or pathological signs were observed in anyof the groups during the experiment and at sacrifice. The animalsappeared healthy and did not show any weight loss. The implantationsites were clean and normal without any swelling and the remnants of theimplanted polymers were easily retrieved. At the implant site of the newpolymers, a small amount of polymer remnants (30-40% of the originalmass) in the form of a soft mass was seen. The animals implanted withpoly(FAD-SA) 50:50 had solid remnants in the site of about 70% of theoriginal implant size. About 20% of the PSA remained at the implant siteafter 12 days, and the Vicril polymer remained intact. Histopathologyexamination of tissue specimens from the area confined to the tissue indirect contact with the polymer device showed mild inflammation whichwas rated 2 in a scale from 1 to 5 where: 1-- resembles no irritation;2--slight inflammation; 3--moderate; 4--marked; and 5--severeinflammation. No encapsulation was found with any of the samples.

A second group of rats which were implanted with the polymers undersimilar conditions were completely eliminated from the site after 12weeks. In comparison, Vicril polymers remained almost intact,Poly(FAD-SA) 50:50 was only 60% eliminated.

This experiment indicates that the new fatty acid based polymers arebiocompatible. The elimination time in vivo of these polymers is shorterthan for the FAD-based polymers.

The rat model has been considered highly predictable of human responsefor toxicant elimination (Ratacliffe et al, 1984) and biocompatibility.(Laurevcin et al, 1990).

5. In vitro hydrolysis

The hydrolysis of the 1:1 copolymers with SA was studied by:

(a) weight loss of the sample;

(b) monitoring the change of molecular weight by gel permeationchromatograph (GPC);

(c) monitoring the disappearance of the anhydride linkage and theformation of carboxylic acid by FTIR spectroscopy; and

(d) the release of sebacic acid from the polymer by HPLC analysis.

The hydrolysis studies were conducted in 0.1M phosphate buffer pH 7.4 at37° C. using rectangular samples 3×5×8 mm in size and weighing about100-150 mg. The samples were taken out from the buffer at different timeintervals and were weighed after being dried thoroughly in the oven. Thepercent weight loss of the sample and the transformation of theanhydride bond to acid as a function of time are shown in FIG. 1. Thechange in molecular weight was monitored by GPC showing a drastic dropin molecular weight in the first 24 hours and then stabilized at about6,000-7,000 from then on. The samples were observed visually for thechanges in the external appearance. At any stage of the experiment, thesamples did not crumble nor were there any cracks visible.

6. In vitro enzymatic degradation.

The enzymatic degradation of these new monomers were compared to thoseof the oligomerized fatty acids. The monomers RAM, HSAM, HSAS, FAD, andFAT (200 mg) were mixed in a solution containing esterase (2 ml,containing 50 units of esterase from porcine liver, Sigma ChemicalCompany, St. Louis, Missouri) and were incubated for 24 hours at 37° C.The monomers or their degradation products were extracted withchloroform and analyzed by ¹ H NMR. The ¹ H NMR spectra of the FAD andFAT monomers were identical before and after treatment. The RAM, andHSAS monomers contained about 10% ricinoleic acid or 12-hydroxy stearicacid, respectively. This study demonstrates the biodegradability of thenew monomers compared to the oligomerized fatty acid monomers.

7. In vitro drug release.

Ciprofloxacin (5% by weight) was incorporated in rectangular tablets(3×5×8 mm in size and 200 mg weight) of poly(RAM-SA) 1:1, P(HSAM:SA)1:1,P(HSAS:SA)1:1, P(FAD:SA)1:1 and poly(suberic anhydride) by the meltmethod. In vitro drug release was determined in phosphate buffer pH 7.4at 37° C. Ciprofloxacin concentration was determined by UV detection at272 nm. The results are shown in FIG. 2. The drug release followed afirst order kinetics (r² =0.89-0.99) with a fast release during thefirst 10 days and a slow release thereafter.

In a second experiment, Ciprofloxacin (5% weight) was incorporated inrectangular tablets (3×5×8 mm in size and 20 mg weight) of poly(RAM-SA)of various compositions by the melt method. In vitro drug release wasdetermined in phosphate buffer pH 7.4 at 37° C. Ciprofloxacinconcentration was determined by UV detection at 272 nm. The results areshown in FIG. 3. The drug release followed a first order kinetics (r²=0.96) with a fast release during the first 10 days and a slow releasethereafter. The drug release rate was increased with the increase in thesebacic acid content in the polymer; however, a small difference in therelease profile was found for the polymers composed of 40 to 80% sebacicacid (SA). Similar results were reported for the FAD-SA copolymers.

The preparation of dimer oleic acid or dimer erucic acid (FAD) containstwo steps. In the first step, oleic acid or erucic acid undergo acoupling reaction using clay as a catalyst. In the second step, theproduct is hydrogenated to saturate the double bonds in the product.During the first step, many by-products are formed, including trimersand tetramers, that are difficult to remove. Also, the FAD productcontains cyclic and aromatic by-products which counts to about 30% ofthe Priipol 1004 and 1009 products which are the most available pure FADproducts (based on producer, Unicema, information). The product of thepresent invention contains only one component, the linear diacid monomerwhich is synthesized in a single esterification step (condensationreaction in general) which cannot form other oligomers or cyclicmaterials, but the linear diacid as described herein.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology which has been used is intended to bein the nature of words of description rather than of limitation.

Obviously, many modifications and variations of the present inventionare possible in light of the above teachings. It is, therefore, to beunderstood that within the scope of the appended claims the inventionmay be practiced otherwise than as specifically described.

                  TABLE 1                                                         ______________________________________                                        Molecular weights and thermal characterization                                of fatty acid ester polymers                                                                      Melting   Tm.sup.c                                                 Molecular weight                                                                         point.sup.b                                                                             T.sub.max                                                                            .increment.H.sup.d                       Polymer of Mw       Mn      (°C.)                                                                          (°C.)                                                                       (J/gm)                               ______________________________________                                        RAM        27,800   11,400  viscous oil                                                                           --   --                                   HSAM       29,500    9,400  semisolid                                                                             --   --                                   HSAS       15,200    8,700  semisolid                                                                             --   --                                   RAM:SA 10:90                                                                             10,500    7,200  72-76   86.18                                                                              98.59                                RAM:SA 20:80                                                                              8,500    6,200  68-74   81.33                                                                              108.99                               RAM:SA 30:70                                                                             14,000   10,800  68-70   79.33                                                                              103.02                               RAM:SA 40:60                                                                              6,200    5,000  65-70   76.63                                                                              65.81                                RAM:SA 50:50                                                                             135,200  12,900  56-62                                             HSAM:SA 50:50                                                                            32,000   11,600  65-68   67.31                                                                              50.59                                HSAS:SA 50:50                                                                            28,700   13,000  68-70   70.39                                                                              78.45                                PSA        465,800  23,400  83      88.64                                                                              131.88                               ______________________________________                                         a. Polymers synthesized by melt condensation.                                 .sup.b Melting points determined on an Electrothermal melting point           apparatus.                                                                    .sup.c Melting transition temperature determined by DSC.                      .sup.d Degree of crystallinity is obtained from the .increment.H              determined by DSC, larger .increment.H values insinuate higher degree of      crystallinity.                                                           

Table 2. Other characteristics of polymers

IR. All polymers had typical IR peaks at 2900, 2850, 1805, and 1740cm⁻¹. ¹ H-NMR of homopolymers of RAM,HSAM,HSAS, and 1: 1 copolymers withSA (d ppm): PRAM: 6.27 (dd, 2H, CO--CH═CH--CO), 5.43 (m, 1H, CH═CH),5.31 (m, 1H,CH═CH), 4.96 (m, 1H, methine), 2.47 (t, 2H when prepolymeris head-to-tail, CH₂ --COO--), 2.42 (t, 2H when prepolymer ishead-to-head, CH₂ --COO--), 2.30 (m, 2H, CH═CH--CH₂ --CH₂ --), 2.00 (dd,2H,CH--CH₂ --CH═CH), 1.60 (m, 4H, CH₂ --CH₂ --COOCO-- andCH═CH--COO--CH--CH₂ --CH₂), 1.29 (brd, 16H, aliphatic methylenes), 0.88(t, 3H, CH₂ --CH₃). PHSAS :4.88 (quintet, 1H, methine), 2.76 (t, 2H,COOCO--CH₂ --CH₂ --COO--CH), 2.64 (t, 2H, COOCO--CH₂ --CH₂ --COO--CH),2.43 (t, 2H, CH₂ --COOCO), 1.65 (m, 4H, CH₂ --CH--OCO--CH₂), 1.51 (brrm,2H, CH₂ --CH₂ --COOCO), 1.25 (m, 22H, aliphatic methylenes), 0.88 (t,3H, CH₂ --CH₃). PHSAM: 6.30 (dd, 2H, CO--CH═CH--CO), 4.98 (quintet, 1H,methine), 2.52 (t, 2H when prepolymer is head-to-tail, CH₂ --COO--),2.42 (t, 2H when prepolymer is head-to-head, CH₂ --COO--), 1.58 (m, 4H,CH₂ --CH₂ --COOCO-- and CH═CH--COO--CH--CH₂ --CH₂), 1.24 (brd, 22H,aliphatic methylenes), 0.83 (t, 3H, CH₂ --CH₃). P(RAM-SA)1:1 : 6.27 (s,2H, CO--CH═CH--CO), 5.45 (brm, 1H,COOCO--CH═CH--COO--CH), 5.33 (brm, 1H,COOCO--CH═CH--COO--CH), 4.98 (brm, 1H, methine), 2.53 (t, 2H when RAMprepolymer is head-to-tail, CH₂ --COO--), 2.44 (t, 2H when RAMprepolymer is head-to-head, CH₂ --COO--), 2.35 (m, 2H, --O--CH--CH₂--CH═CH--CH₂ --), 2.09 (dd, 2H,--O--CH--CH₂ --CH═CH--), 1.65 (m, 4H, CH₂--CH₂ --COOCO-- and CH=CH═CH--COO--CH--CH₂ --CH₂), 1.29 and 1.25 (twobrs, aliphatic methylenes from RAM and from SA), 0.87 (t, 3H, CH₂--CH₃). P(HSAS-SA)1:1 : 4.88 (quintet, 1H, methine), 2.77 (t, 2H,COOCO--CH₂ --CH₂ --COO--CH), 2.66 (t, 2H, COOCO--CH₂ --CH₂ --COO--CH),2.44 (t, 6H, CH₂ --COOCO), 1.65 (m, 6H, CH₂ --CH--OCO--CH₂), 1.51 (brm,4H, CH₂ --CH₂ --COOCO), 1.32 (m, 12H, CH₂ --CH₂ --CH₂ --CH₂ --COO), 1.25(m, aliphatic methylenes), 0.88 (t, 3H, CH₂ --CH₃). P(HSAM-SA)1:1 : 6.30(brm, 2H, CO--CH═CH--CO), 4.98 (brm, 1H, methine), 2.44 (t, CH₂--COO--), 1.62 (tt, 2H, CH₂ --CH₂ --COOCO--), 1.56 (dt, 4H, --CH₂--COO--CH--CH₂ --(CH₂)₄ --CH₃ and --CH₂ --COO--CH--CH₂ --(CH₂)₉--COO--), 1.32 and 1.25 (two brd, aliphatic methylenes from HSAM andfrom SA),0.88 (t, 3H, CH₂ --CH₃).

                  TABLE 3                                                         ______________________________________                                        Mechanical properties of fatty acid polymers                                                              Tensile                                                                              Compression                                Polymer                     Strength                                                                             at break                                   composition                                                                              Mw       Mn      (MPa)  (%)                                        ______________________________________                                        P(RAM-SA)1:1                                                                             135,200  5,300   3.2    buckled before                                                                breaking                                   P(HSAM-SA)1:1                                                                             4,300   2,100   2.7    22.95                                      P(HSAS-SA)1:1                                                                             9,400   3,300   2.5    20.91                                      P(FAD-SA)1:1                                                                             73,000   5,900   5.7     9.75                                      PSA        18,600   5,800   7.2     1.57                                      ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Data analysis for diacid fat containing lactide copolymers                                      Viscosity                                                                              Melting point                                      Polymer:          (dL/gr)  (°C.)                                       ______________________________________                                        P(LA-RAM-PG)8:1:1 0.22     42-47                                              P(LA-HSAM-PG)8:1:1                                                                              0.15     38-45                                              P(LA-HSAS-PG)8:1:1                                                                              0.20     47-50                                              ______________________________________                                    

REFERENCES

1. Domb et al., Polymeric Biomaterials, Marcel Debker, NY., N.Y.,(1994).

2. Domb et al., Polym. Adv. Technol. 3.279 (1992).

3. Domb et al., Biopolymers 107:1 (1993).

4. Leong et al., Biomed. Mat. Res, 19:941 (1985)

5. Domb and Maniar (1993) J. Polymer Sci. :Part A:Polymer Chem.31:1275-1285

6. Domb and Langer (1987) J. Polym. Sci. Part A: Polym. Chem., 1987,25:3373

7. Ratacliffe et al. (1984) J. Pharm. Pharmacol. 36:431

8. Laurencin et al. (1990) J. Biomed. Mat. Res, 24:1463

We claim:
 1. A monomeric diacid derivative comprising between two andfour fatty acids coupled by a hydrolytically or enzymatically degradablebond whereby said degradable bond degrades in a biological environmentto form naturally occurring fatty acid products.
 2. The derivative ofclaim 1 having the structure ##STR6## wherein R, R¹, and R² arealiphatic alkane organic residues with 0 to 20 carbon atoms and can bethe same or different, X is an enzymatically or hydrolyticallydegradable bond.
 3. The derivative of claim 1 derived from monoglyceridedicarboxylic acid and having the structure ##STR7## wherein x is aninteger from 5 to 25; y is an integer from 1 to 12; and Z includes thesubstitution groups CO, CO--O, CO--NH.
 4. The derivative of claim 1derived from tartaric acid and having the structure ##STR8## wherein xis an integer from 5 to 25 and Z includes the substitution groups CO,CO--O , CO--NH.
 5. The derivative of claim 1 derived from a dicarboxylicacid fat and having the structure ##STR9## wherein y is an integer from1 to 12; v+w are integers which total 25; and M includes thesubstitution groups O--CO, O--CO--O, O--CO--NH, O--PO₂ --O, NH--CO. 6.The derivative of claim 1 synthesized from ricinoleic acid and maleicanhydride forming ricinoleic acid maleate hydrogenolated to form12-hydroxystearic acid succinate with the structure ##STR10##
 7. Thederivative of claim 1 synthesized from the reaction between12-hydroxystearic acid and maleic anhydride with the structure of##STR11##
 8. A monomeric diacid derivative of claim 1 wherein saiddegradable bond is an ester, amide, urethane, urea or carbonate bond. 9.A method for synthesizing a biodegradable polymer containinghydrolyzable diacid fats comprisingpreparing a highly pure prepolymer ofmonomeric diacid derivative comprising between two and four fatty acidscoupled by a hydrolytically or enzymatically degradable bond;polymerizing one highly pure prepolymer at a temperature and reactiontime to form a polyanhydride or polyester of an appropriate molecularweight; and stopping said polymerization when the appropriate molecularweight product is obtained.
 10. The method of claim 9 wherein acopolymer is formed from two highly pure prepolymers polymerizedtogether.
 11. A plasticizing diacid derivative comprising between twoand four fatty acids coupled by a hydrolytically or enzymaticallydegradable bond whereby said degradable bond degrades in a biologicalenvironment to form naturally occurring fatty acid products.
 12. Thediacid derivative of claim 11 wherein the diacid derivative is based onricinoleic acid maleate.